Regulation of the DYRK1A kinase by the Down Syndrome Cell Adhesion Molecule DSCAM - ABSTRACT: Candidate and Environment: The Fuerst Lab will conduct genetic, molecular and morphological
experiments related to the Aims of this proposal at the University of Idaho. The Fuerst lab team has extensive
expertise centered on the cell biology and genetics of neural development. Fuerst identified Dscams as the first
molecules that regulate mosaic organization of neurons and developed many of the genetic reagents for use in
these experiments. Here we will build on our foundation of experience studying Dscam genes to probe the
function of downstream signaling networks in neural development. Research Proposal: Developing neurons
utilize a range of molecular cues to organize into neural tissues and organs. We and others have previously
reported that Down syndrome cell adhesion molecule (Dscam) genes are required for normal development of
neural tissues. How Dscam genes mediate a wide range of cellular responses even within a single cell type is
an active area of research. In our preliminary studies we found that overexpression of Dyrk1a, whose product
interacts biochemically with DSCAM, phenocopies Dscam loss of function. Further we report a redistribution of
cellular DYRK1A protein in the Dscam loss of function retina and brain. Based on these observations and the
genes’ known antagonistic roles in either promoting or inhibiting developmental cell death, we hypothesize
that DSCAM interactions on the cell surface antagonize DYRK1A activity by controlling its subcellular
localization. We test this hypothesis in two specific Aims. Aim 1: Pilot genetic studies indicate that either
decreasing Dscam dosage or increasing Dyrk1a dosage results in mistargeting of retinal neuron neurites. A
similar increase in Dyrk1a expression in the Ts65Dn trisomic mouse models results in a wild type targeting
phenotype, however, suggesting a factor or factors in the Down syndrome critical region (DSCR) are
compensating for Dyrk1a overexpression. First, we will test if increasing Dyrk1a expression in the Ts65Dn
mouse model above the expression of other DSCR genes is sufficient to restore Dyrk1a overexpression
neurite targeting defects (Aim 1A). Second, we will test if reducing Dscam expression in Ts65Dn mice to wild
type levels restores the Dyrk1a overexpression phenotype (Aim 1B). Aim 2: We will extend our pilot study
generated in retina into the brain at large. We will test if DYRK1A localization is developmentally dynamic in
the brain (Aim 2A), if DSCAM regulates DYRK1A localization in the brain (Aim 2B) and if Dscam expression is
sufficient to modify DYRK1A accumulation or localization in vitro (Aim 2C).
Long-term goals: Our long-term goal is to understand how events at the cell surface are transduced to
generate different cellular responses. This R03 will facilitate completion and publication of a pilot study, the
results of which will inform experiments to understand how regulation of DYRK1A localization impacts its
function in development and disease.
Significance: Understanding why mutation or overexpression of genes involved in neural development
can present with a variety of signs and symptoms in people will require us to also understand the functions of
the affected genes with the long-term goal of developing clinical interventions. Here we explore the interaction
between two interacting genes in the Down Syndrome critical region, relevant to studies and treatments
focusing on either single gene. Understanding the downstream signaling pathways utilized by surface
receptors will be essential to help scientists and clinicians pinpoint strategies to treat human diseases.
